Method for producing 5-fluorouracil

ABSTRACT

The present invention concerns the method for producing 5fluorouracil. In accordance with the said method uracil is brought to interact with fluorine in diluent medium which partly or completely dissolves uracil without interacting with fluorine, in an atmosphere of inert gas with subsequent separation of the formed end product. It is preferable to employ acetic acid as diluent, and nitrogen as the inert gas. The end product 5fluorouracil finds wide application in cancer therapy of the mammary gland and gastrointestinal tract. It is also the initial product for the synthesis of 5-fluor-2&#39;&#39;desoxyuridine and N-2&#39;&#39;-tetrahydrofuryl-5-fluorouracil which are also employed in medicine as antitumor agents. Besides the above, 5-fluorouracil finds application for biochemical investigations.

United States Patent Knuniants et al.

3,682,917 Aug. 8, 1972 METHOD FOR PRODUCING 5- FLUOROURACIL [72]Inventors: Ivan Ljudvigovich Knuniants, Kotelnicheskay naberezhnaya, 1/l5, kv. 336; Lev Solomonovich German, Serpukhovskaya ulitsa, 31, korpus9, kv. 303; Natalia Borisovna Kazmina, poselok Malaklovka Moskovskoioblasti, ulitsa Tsvetnaya 5, all of Moscow, U.S.S.R.

[22] Filed: March 25, 1970 [21] Appl. No.: 22,705

[52] US. Cl ..260/260, 260/694 [51] Int. Cl. ..C07d 51/30 [5 8] Field ofSearch ..260/260, 694

[5 6] References Cited UNITED STATES PATENTS 2,013,030 9/1935 Calcott etal. ..260/694 2,186,917 1/1940 Gaylor ..260/694 Primary ExaminerAlexMazel Assistant Examiner-Anne Marie T. Tighe Attorney-Holman & Stern[57] ABSTRACT The present invention concerns the method for It is alsothe initial product for the synthesis of S-fluor- 2-desoxyuridine andN-2-tetrahydrofuryl-5-fluorouracil which are also employed in medicineas antitumor agents. Besides the above, S-fluorouracil finds applicationfor biochemical investigations.

4 Claims, No Drawings 1 METHOD FOR PRODUCING S-FLUOROURACIL The presentinvention relates to improvements in the method for producing5-fluorouracil which is an effective antimetabolite used as an agent formammary gland and gastrointestinal cancer therapy. S-fluorouracil isalso the initial product in the synthesis of 5- fluor-2'-desoxyuridineand N-2'-tetrahydrofuryl-5- fluorouracil employed in medicine asantitumor preparations.

Besides the above, 5-fluorouracil is widely employed for biochemicalinvestigations.

The known method for obtaining 5-fluorouracil consists in condensingethylmonofluoroacetate with ethyl fonnate in the presence of potassiumethoxide with the formation of ethylformylfluoroacetate enolate,condensing the latter with alkylisothyuronium salt and subsequenthydrolysis of the product obtained. The yield of the end productconstitutes 18-30 percent by weight based on initial ethylmonofluoroacetate. See US. Pat. No. 2,802,005, R. Duschinsky, E. Pleven,Ch. Heidelberger, J. Am. Chem. Soc. 79, 4559 1957/ and l. Feldman etal., Med. Prom. SSSR, 19/3, 12/ 1965.

The drawbacks of the above mentioned method are the low yield of the endproduct and the multi-stage process.

The particular object of the present invention is to ensure a higheryield of the end product.

Another object of the present invention is to simplify the technology ofthe process employed.

This particular and other objects of the invention were attained by thismethod for producing 5-fluorouracil wherein, in accordance with thisinvention uracil is brought to interact with fluorine, in diluentmedium, which partly or completely dissolves uracil, and does notinteract with fluorine, in an inert gas atmosphere, with subsequentrecovery of the formed end product.

As diluent it is advisable to use acetic acid or hydrogen fluoride asthis serves to simplify the technology of separation and purification ofthe end product.

It is preferable to employ nitrogen as the inert gas.

With a view to increase the yield of the end product with acetic acidbeing used as diluent, it is advisable to carry out the process at20-25C, whereas when anhydrous hydrogen fluoride is employed as diluentit is advisable to carry out the process within C.

The present invention may be realized as follows.

Uracil is mixed with the diluent which may be, for example, acetic acid,hydrogen fluoride, sulphuric acid, water etc. It is advisable to carryout the process in acetic acid or hydrogen fluoride media. Then fluorinewith inert gas, nitrogen for example, is introduced into the reactionmixture.

The temperature at which the process is carried out is determined by theselected diluent. The end of the reaction is determined by thedisappearance of the initial uracil in the reaction mixture. Control iscarried out by method of thin layer chromatography on aluminium oxide lIstage activity acetone-water system 1:7.

At the end of the reaction the diluent is distilled off and the residuewashed with ethyl ether, for example, then, if acetic acid was employedas diluent, it is crystallized from water.

The yield of the end product is 52-55 percent by weight of theory, basedon uracil. When hydrogen fluoride is employed as diluent the residue,after the diluent is distilled off, is treated with alkali, the solutionis filtered, the filtrate is acidified by concentrated hydrochloricacid, cooled, the deposit is separated, washed in ether, dried, and thencrystallized from water.

The yield of the end product is 6-8 percent by weight of theory, basedon uracil. The method offered by this invention permits to increase theyield of the end product, to simplify the technology of the process i.e.the process is carried out in one stage and permits the exclusion of theuse of a highly toxic initial productethyl monofluoroacetate.

For a better understanding of the invention the following examples aregiven by way of illustration of the method.

EXAMPLE 1 Through a vigorously stirred suspension consisting of 2 g0.018 mole uracil in 170 cc acetic acid a mixture of F and N is passedfor 12-15 hours. F and N are taken in voluminal ratio of 1:5 at atemperature of 20C, and at a speed of 200-300 cc per hr.

The end of the reaction is determined by the disappearance of initialuracil in the reaction mixture thin layer chromatography method on A1 01 1 stage activity acetone-water system 1:7.

The reaction mixture is concentrated by evaporation in vacuum, theresidue is subjected to manifold washing with etrer, crystallized fromwater with activated coal and dried in vacuum over P 0 at C.

The yield is 1.2g 52 percent of theory, based on uracil S-fluorouracil,melting point 282283 with decomposition, the temperature corrected. Themelting point of the mixed sample with previously known 5- fluorouracil,obtained according to the known method showed no depression, meltingpoint 282283 with decomposition, the temperature corrected.

The infra-red spectrum of the sample obtained is completely identical tothe infra-red spectrum of the previously known compound: 760 weak; 820medium; 890 weak; 950 weak; 1,000 weak; 1,180 weak; 1,220 weak; 1,250strong; 1,350 weak; 1,430 medium; 1,510 weak; 1,670 strong; 1,730 weak;2,000 weak; wide band 2,800-3,600 cm. Ultra-violet spectrum: 265-266 0.1N HCI.

Data cited by literary sources: melting point 28228 3 withdecomposition. Ultra-violet spectrum: 265-266 0.1 N HCI.

EXAMPLE 2 A mixture of fluorine and nitrogen taken in a ratio of 1:4 byvolume is passed at vigorous stirring for a period of 7 hours through asolution of 2.8 g 0.025 mole uracil in cc anhydrous hydrogen fluoride at0 +5C.

The process is continued until the initial uracil in reaction mixturedisappears. On completion of the reaction the hydrogen fluoride isdistilled off at 0C in a current of CO the residue is dissolved inaqueous KOH, the solution is filtered, the filtrate is then acidified byconcentrated hydrochloric acid up to pH 2 and cooled. The crystallineprecipitate is separated, washed with ether, dried and crystallized fromwater to obtain 0.2 g-6. 1 percent of theory-S-fluorouracil which isidentical to that described in example 1 i.e., by melting point,infra-red spectrum.

3. A method for producing 5-fluorouracil comprising reacting uracil withfluorine in hydrogen fluoride at a temperature of from about 0 to about5C in an inert gas atmosphere.

4. The method of claim 3 wherein said inert gas is nitrogen.

2. The method of claim 1 wherein said inert gas is nitrogen.
 3. A methodfor producing 5-fluorouracil comprising reacting uracil with fluorine inhydrogen fluoride at a temperature of from about 0* to about 5*C in aninert gas atmosphere.
 4. The method of claim 3 wherein said inert gas isnitrogen.